The puzzling origin of the smallpox vaccine

Hezne Ezaty Abu Hasan, 17 Oct 2017

Edward Jenner, father of immunology, successfully eradicated smallpox from 1966 to 1977.

In 1796, while still in medical school, Edward Jenner from Gloucestershire noticed that milkmaids who had contracted a disease called cowpox, which caused blistering on cow’s udders, did not catch smallpox. Smallpox caused severe skin eruptions and dangerous fevers and reclaimed many lives. Cowpox, on the other hand, was relatively harmless and only caused mild symptoms in the milkmaids.

Following his observation, in May 1796, Jenner tested his hypothesis by taking fluid from milkmaid Sarah Nelmes’ cowpox blister and scratched it into the skin of James Phipps, his gardener’s eight-year-old son. Phipps had a fever and a single blister, but soon recovered. Later in July that year, Jenner inoculated Phipps again – this time with smallpox matter. No disease developed, Phipps was immune to smallpox.

Doctors and researchers replicated Jenner – the father of immunology – and his success by mass eradicating smallpox from 1966 to 1977. In 1980, smallpox, which had been around for 3,000 years and claimed half a billion lives in the 20th century alone, was successfully eradicated from the world. The vaccine evolved over time with the modern vaccine being called vaccinia, and throughout time the vaccine remained to have a puzzling host.

Horsepox, not cowpox, in smallpox vaccine

Historians and physicians believe the smallpox vaccine is made up of cowpox virus, a cousin of the smallpox virus. However, this leaves much room to wonder about Jenner’s original source of virus. He himself said that it could be horsepox, which could infect cows.

A recent finding, published in the New England Journal of Medicine has shed new light on the subject. Researchers led by the Robert Koch Institute in Berlin, Germany has analysed a 1902 vial containing one of the earliest smallpox vaccine. The vaccine was produced by H.K. Mulford Co. from Philadelphia—which we now know as Merck & Co.—and found the virus used in that inoculation to be related to horsepox, rather than cowpox. The sequence came up with strong 99.7% similarities.

The 1902 smallpox vaccine produced by H.K. Mulford & Co. that was analysed to reveal a virus origin of horsepox. Photo credit: The New England Journal of Medicine/STAT News

Clarissa Damaso, an expert in virology and molecular biology from the Federal University of Rio de Janeiro, Brazil and co-author of the study said that it was possible that the viruses were interchangeably used over time. Cowpox, horsepox and smallpox are three different viruses but with the same genus. The modern vaccinia is not related to either cowpox or horsepox.

This new finding provides evidence "of the suspected role of horsepox in the origin of the smallpox vaccine, a role that was suspected even by Jenner himself," the study states.

Recreating smallpox

Prior to the recent published findings of the smallpox vaccine origin in the New England Journal of Medicine, scientists in Canada has synthesised horsepox virus for a mere CAD100,000 with half a year’s time and genetic pieces ordered in the mail. The virus was intended to pave a path for better vaccines and even cancer therapeutics.

However, in synthesising the horsepox virus, the group led by virologist David Evans of the University of Alberta in Edmonton, Canada has also recreated the eradicated smallpox virus – a scandalous reason for which Evans’ research has been denied and unpublished. The World Health Organization has forbidden for the full smallpox genome to be reconstructed or to breed live smallpox virus in the lab.

To date, smallpox virus is contained in only two facilities—one in Georgia in the US and one in Novosibirsk, Russia—and has been proven to be of value in developmental research, especially in pancreatic and prostate cancer research. Even without access to the contained smallpox virus, Evans’ study has shown that smallpox can easily make a comeback or even be used in bioterrorism.

On a less grim note, the study does mark "an important milestone, a proof of concept of what can be done with viral synthesis,“ says bioethicist Nicholas Evans of the University of Massachusetts. MIMS